DE69823360T3 - SOLID MEDICAL CONSUMPTION CONTAINING BENZOFURANDERIVATE - Google Patents

Description

The present invention relates generally to a novel pharmaceutical preparation for oral administration containing as active ingredient a benzofuran derivative.

More particularly, the invention relates to a solid pharmaceutical preparation for oral administration containing as active ingredient a benzofuran derivative having antiarrhythmic activity.

The term "benzofuran derivative with antiarrhythmic activity" in the context of the present invention denotes a benzofuran compound. which is selected from those mentioned in the patents US 3,248,401 , US 5,223,510 and EP 338 746 as well as the patent applications WO 98/07996 . WO 89/02892 . WO 90/02743 and WO 94/29289 are described.

From the totality of these compounds, 2-n-butyl-3- [4- (3-di-n-butylaminopropoxy) benzoyl-5-methylsulfonamidobenzofuran or dronedarone and its pharmaceutically acceptable salts, as described in U.S. Pat U.S. Patent 5,223,510 and 2-n-butyl-3- (3,5-dilod-4-diethylaminoethoxy-benzoyl) -benzofuran or amiodarone and its pharmaceutically acceptable salts as described in U.S. Pat U.S. Patent 3,248,401 are described, call.

In the same way, a "solid pharmaceutical preparation" is essentially understood to mean a pharmaceutical preparation which is formed in its entirety from powdery and compressible solid components which are at room temperature and comprise the active ingredient and the carrier materials. wherein these ingredients are substantially in the form of a powder.

Accordingly, pharmaceutical preparations which are referred to as semi-solid and which are formed from substances which, when they are at moderate temperatures (<70 ° C) in paste or wax form, not subject of the invention.

The antiarrhythmic compounds used in the invention, in particular dronedarone and amiodarone in the form of their hydrochlorides are characterized by their low solubility in an aqueous medium.

For example, the solubility curve of the hydrochloride of dronedarone at room temperature shows a maximum solubility at a pH of about 3 to 5 of about 1 to 2 mg / ml, depending on the pH, but very low at pH values in the range of 6 to 7 since it is only 10 μg / ml at a pH of 7.

The solubility of the hydrochloride of amiodarone is 0.3 to 0.9 mg / ml at room temperature in the pH range of 3 to 4 and a few μg / ml at a pH of 7.

Accordingly, it is possible to dissolve 400 mg of the hydrochloride of dronedarone in 200 ml of an aqueous medium buffered to a pH of 4 (0.1 M aqueous solution of NaH ₂ PO ₄ ).

On the other hand, the hydrochloride of dronedarone precipitates from this medium. if it is diluted by a factor of 1 to 10 with an aqueous solution buffered to pH 7 (aqueous 0.1M Na ₂ HPO ₄ solution) (final medium pH: 6.7).

These solubility conditions, which are comparable to those found in the gastrointestinal tract, suggest that the hydrochloride of dronedarone finds favorable acidic conditions in the stomach for its solution, but, conversely, upon entry into the intestine, a medium of pH Value of 6 to 7 that is, a medium in which it no longer dissolves, but fails.

This behavior in the intestinal medium may allow the explanation of the low bioavailability of the hydrochloride of dronedarone in vivo and the differences observed after administration in the presence or in the absence of food.

In fact, it has been observed that the bioavailability of the hydrochloride of dronedarone in dogs and humans is increased after ingestion of food, especially fats, which can greatly affect the kinetics of precipitation of this drug and favor the emulsification of this material ,

Since the absorption of food causes the secretion of bile salts which are anionic surfactants, these could, in an important way, affect the solution of the hydrochloride of dronedarone.

In contrast, the studies carried out with respect to this effect have shown that the active ingredient precipitates in the presence of bile salts such as sodium taurocholate.

For the provision of an oral pharmaceutical preparation of dronedarone, amiodarone or their pharmaceutically acceptable salts, which is suitable for preventing the precipitation of the active ingredient in neutral medium and for reducing the variation in the plasma absorption of that active agent, that is to say for providing it an acceptable bioavailability independent of the presence of food is therefore of essential interest.

It has now surprisingly been found that the combination of a nonionic hydrophilic surfactant with dronedarone and amiodarone or their pharmaceutically acceptable salts makes it possible to maintain the solution of this drug in neutral medium and to reduce in man his fluctuations in absorption in the blood.

This finding is all the more surprising as preliminary dog studies have failed to demonstrate that a nonionic, hydrophilic surfactant would be capable of increasing fasted bioavailability of dronedarone hydrochloride and, similarly, fluctuations reduce the plasma absorption of this drug.

Accordingly, the invention relates to a solid pharmaceutical preparation for oral administration comprising a benzofuran derivative having antiarrhythmic activity or one of its pharmaceutically acceptable salts as active ingredient and a pharmaceutically acceptable nonionic hydrophilic surfactant optionally in combination with one or more pharmaceutical excipients.

This pharmaceutical preparation may be in any solid pharmaceutical form suitable for administration by oral route, such as optionally divisible tablets, granules, gel capsules. Powder and unit sachets.

Accordingly, a further aspect of the invention extends to the above-mentioned orally administered pharmaceutical preparation in the form of a tablet, a granule, a gel capsule or a powder.

• • Ethylenoxid/Propylenoxid-Copolymere, die nachfolgend als Poloxamer bezeichnet werden, wie Poloxamer 124, das unter der Marke SYNPERIONIC® PE/L44 erhältlich ist; Poloxamer 188, das unter der Marke PLURONIC® F68 oder SYNPERONIC® PE/F68 vertrieben wird; Poloxamer 237, welches unter der Marke PLURONIC® F87 oder SYNPERIONIC® EP/F87 vertrieben wird: Poloxamer 338, welches unter der Marke SYNPERIONIC® PE/F108 im Handel vertrieben wird oder Poloxamer 407 welches unter der Marke PLURONIC® F127 SYNPERIONIC® PE/F127 oder LUTROL® F127 vertrieben wird.
• • Polyethoxylierte Rizinusöle, wie sie im Handel unter der Marke CREMOPHOR® RH40 vertrieben werden.
• • Ethoxylierte Polysorbate, wie Polysorbat 20, Polysorbat 40, Polysorbat 60 und Polysorbat 80, die unter den Marken TWEEN® 20, TWEEN® 40, TWEEN® 60 bzw. TWEEN@80 erhältlich sind.
• • Oder aber auch Hydroxystearate von Polyethylen, wie Hydroxystearat von Polyethylen 660, welches unter der Marke SOLUTOL® HS15 vertrieben wird.

Als bevorzugtes oberflächenaktives Mittel kann man Poloxamer 407 nennen.The nonionic hydrophilic surfactant used in the preparation of the invention may be selected from:

• Ethylene oxide / propylene oxide copolymers, hereinafter referred to as poloxamer, such as Poloxamer 124 available under the trademark SYNPERIONIC® PE / L44; Poloxamer 188 sold under the trademark PLURONIC® F68 or SYNPERONIC® PE / F68; Poloxamer 237, which is marketed under the trade mark PLURONIC® F87 or SYNPERIONIC® EP / F87: Poloxamer 338, which is marketed under the trade mark SYNPERIONIC® PE / F108 or Poloxamer 407 which is marketed under the trade mark PLURONIC® F127 SYNPERIONIC® PE / F127 or LUTROL® F127.
• Polyethoxylated castor oils, as sold commercially under the trademark CREMOPHOR® RH40.
• • Ethoxylated polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, available under the trademarks TWEEN® 20, TWEEN® 40, TWEEN® 60, and TWEEN @ 80, respectively.
• • Or also hydroxystearates of polyethylene, such as hydroxystearate of polyethylene 660, which is marketed under the trademark SOLUTOL® HS15.

As a preferred surfactant Poloxamer 407 can be mentioned.

Usually, the nonionic hydrophilic surfactant in question is incorporated in an amount of from 1% to 50% by weight, based on the active ingredient in the form of the base, in the solid preparations of the present invention, regardless of whether the pharmaceutical form is a unitary form or not, and whether it is adapted for their conditioning.

For the preparation of the solid preparations in the form of tablets or in the form of a gel capsule, for example, 1% by weight to 20% by weight of the surface-active agent, based on the active ingredient in the form of the base, is used, preferably 5% to 15%.

As a non-limiting example, the amount of active ingredient may vary from 50 to 500 mg per administration unit in the form of a tablet, involving the incorporation of an amount of the surfactant between 0.5 and 100 mg. These amounts of surfactant have proven to be fully acceptable with pharmaceutical forms such as tablets or gel capsules, the sizes of which are compatible with oral administration.

Preferably, the solid pharmaceutical preparations according to the invention, which are present for example in the form of a tablet or a gel capsule, 200 to 400 mg of the active ingredient, calculated as the form of the base, and 5% to 15%, especially 10 wt .-% of the nonionic, hydrophilic surface-active Contain by means of the active ingredient in the form of the base.

For conditioning in the form of a unit sachet powder, one may use from 1% to 50% by weight of the nonionic hydrophilic surfactant, based on the active ingredient in the form of the base.

In addition to the surface-active agent in question, the preparations according to the invention in solid form contain further pharmaceutical carrier materials. commonly used in the preparation of orally administered pharmaceutical forms.

These substances are fully known to those skilled in the art, who can easily select them depending on the kind of the selected oral preparation to be given.

By way of non-limiting example, mention may be made of binders which are generally cellulose derivatives, such as methylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, or else the macrogols, such as Macrogol 6000; Fluidity improvers such as colloidal silica; Vinylpyrrolidone polymers or copolymers, such as polyvinylpyrrolidone: diluents, such as lactose or mannitol; Starches, such as wheat starch or corn starch; Lubricants, such as magnesium stearate or sodium stearyl fumarate.

The preparations according to the invention can be prepared by using known procedures, which include in particular the dry or wet granulation methods by melting or by direct compression to form tablets.

For example, tablets may be prepared by wet granulation by mixing in an initial stage the ingredients including the active ingredient and the surfactant except for a lubricant.

Subsequently, the measures of wetting with purified water, drying and calibrating the resulting granules, adding a lubricant, and compressing or directly introducing into gel capsules are carried out.

According to variants of this method:

1. a) mixing in an initial stage, the total of the ingredients including the active ingredient with the exception of the surfactant and the lubricant and then performs the measures of wetting with an aqueous solution of granulation surfactant, drying, calibration, treatment with the lubricant and compressing or direct introduction into gel capsules or
2. (b) mixing in an initial stage all the constituents, including the active substance and the surfactant, with the exception of the binder and the lubricant, followed by the measures of wetting with an aqueous solution of the binder, granulation, drying, calibration, treatment with the lubricant and the compression or direct introduction into gel capsules.

It is also possible to modify these methods by applying a continuous granulation process which uses the technique of an air fluidization bed in the wetting stage.

On the other hand, it is also possible to use a method in which, in an initial stage, the entirety of the ingredients except for the lubricant is heated, which is heated to a temperature in the range of 60 ° C to 65 ° C. Then, the granulation by heat, calibration after cooling, treatment with the lubricant and compression or direct introduction into gel capsules are carried out.

The dry granulation method first mixes all of the ingredients comprising the active ingredient and the surfactant except for the lubricant, and then performs the measures of sieving, compacting, calibrating the lubricant treatment, and compressing or pouring directly into gel capsules ,

Finally, one can perform a direct compression by performing the following measures: mixing the ingredients, namely the active ingredient and the surfactant without the lubricant, then sieving and mixing followed by treatment with the lubricant and finally compression or direct loading into gel capsules.

The characteristics and advantages of the preparations according to the invention to be administered orally will become apparent in the light of the following description with reference to particular orally administered preparations, which are given as comparative examples and with reference to the accompanying drawings.

Trial of the solution at a pH of 6.7

Active ingredient alone

Solutions of 2 mg / ml of the hydrochloride of dronedarone are prepared in an acid phosphate buffer medium (NaH ₂ PO ₄ ) with a pH of 4.5 for 2 hours at 37 ° C. in the presence or in the absence of x% of the nonionic to be investigated Hydrophilic surfactant, calculated as the weight based on the active ingredient in the form of the base.

Subsequently, this solution is diluted by a factor of 1:10 in a neutral phosphate medium (Na ₂ HPO ₄ + NaH ₂ PO ₄ ), the pH of the final solution being 6.7.

After 2 hours at 37 ° C filtered on a filter of the brand ACRODISC® (5 microns) and determines the amount of active ingredient in solution by UV spectrometry.

In this way you get the following results: Surfactant % % of the dissolved hydrochloride of dronedarone TWEEN® 20 50 65 TWEEN® 40 50 63 TWEEN® 60 50 74 TWEEN® 80 50 69 SYNPERONIC® PE / F68 50 74 SYNPERONIC® PE / F87 50 75 SYNPERONIC® PE / F127 50 95 CREMOPHOR® RH 40 50 64 SOLUTOL® HS 15 50 59 SYNPERONIC® PE / F127 10 78 SYNPERONIC® PE / F127 5 63 - - 5

Active ingredient in the form of a tablet

Solutions of 2 mg / ml of the hydrochloride of dronedarone (expressed as the form of the base) are prepared in an acid phosphate buffer medium (NaH ₂ PO ₄ ) with a pH of 4.5 or 2 mg / ml of the hydrochloride of amiodarone in one Buffer medium with a pH of 3.5.

These solutions are obtained by dissolving tablets of the hydrochloride of dronedarone or the hydrochloride of amiodarone, which do not contain 10% poloxamer 407 (SYNPERONIC® PE / F127) or the ingredient, that is: tablets α (mg) A (mg) Hydrochloride of dronedarone (equivalent to 400 mg of the base) 426 426 methylhydroxypropylcellulose 12 12 Lactose monohydrate 63.6 63.6 Modified cornstarch 60 60 polyvinylpyrrolidone 30 30 Anhydrous colloidal silica 2.4 2.4 SYNPERONIC® PE / F127 - 40 magnesium stearate 6 6 600 640 tablets β (mg) B (mg) Hydrochloride of amiodarone 200 200 Lactose monohydrate 71 71 Modified cornstarch 66 66 Crosslinked polyvinylpyrrolidone 6 6 Anhydrous colloidal silica 2.4 2.4 SYNPERONIC® PE / F127 - 20 magnesium stearate 4.6 4.6 350 370

After a solution time of 2 hours at 37 ° C, the solution is diluted by a factor of 1:10 with a neutral phosphate medium (Na ₂ HPO ₄ + NaH ₂ PO ₄ ), wherein the pH of the final solution is 6.7.

Then the test is carried out as described in section A. above and the results are as follows: % of the dissolved hydrochloride of dronedarone Tablet α 4.6 Tablet A 80 % of the dissolved hydrochloride of amiodarone Tablet β 55 Tablet B 100

These results show that it is possible for these tablets, by incorporating 10% by weight Poloxamer 407 based on the dronedarone base or the hydrochloride of amiodarone, to keep the active ingredient in solution for 80% to 100% during 2 hours.

II. Pharmacokinetic studies

Comparative studies with the hydrochloride of dronedarone were performed on 16 male volunteers, of whom 8 were fasted and the other 8 were not fasted.

These studies were carried out starting from tablets according to the invention: one containing 10% by weight of the surfactant based on the weight of dronedarone in the form of the base (the above tablet A) and the other containing 5% by weight of the same surfactant (the following tablet C) that is: Tablet C mg Hydrochloride of dronedarone (equivalent to 400 mg of the base) 426 methylhydroxypropylcellulose 12 Lactose monohydrate 63.6 Modified cornstarch 60 polyvinylpyrrolidone 30 Anhydrous colloidal silica 2.4 SYNPERONIC® PE / F127 20 magnesium stearate 6 620

1. a) die obige Tablette α
2. b) Gelkapseln, die mit einer Zubereitung der folgenden Zusammensetzung gefüllt sind:

mg Hydrochlorid von Dronedaron (entsprechend 200 mg der Base) 213 Modifizierte Maisstärke 86,2 Lactose- Monohydrat 129,2 Talkum 48 Wasserfreies kolloidales Siliciumdioxid 1,2 Magnesiumstearat 2,4 480 For comparison, preparations were prepared which do not contain a nonionic, hydrophilic surface-active agent, that is to say:

1. a) the above tablet α
2. b) gel capsules filled with a preparation of the following composition:

mg Hydrochloride of dronedarone (equivalent to 200 mg of the base) 213 Modified cornstarch 86.2 Lactose monohydrate 129.2 talc 48 Anhydrous colloidal silica 1.2 magnesium stearate 2.4 480

Each of the volunteers receives a unit dose of the hydrochloride of dronedarone corresponding to 800 mg of the base in the form of the above gel capsules, tablet α, tablet A or tablet C, each unit dose being separated from the following by a period of 7 days.

For each volunteer, the plasma levels at dronedarone are then determined to be 0, 1, 2, 3, 4, 5, 6, 7, 10, 12, 16 and 24 hours after administration and the maximum concentrations of this drug (C max in ng / ml) as well as the area under the curves which is defined by the concentration of the active ingredient as a function of time (AUC in ng / h / ml).

These measures are repeated in a second series of experiments carried out on the two equal groups of 8 alternate volunteers, ie 8 volunteers who perform the test on a fasting basis and vice versa.

1. a) die als „Gelkapsel“ bezeichnete Kurve die mit der Zubereitung in Form einer Gelkapsel erzielte mittlere Plasmakonzentration wiedergibt,
2. b) die als „Tablette α“ bezeichnete Kurve die mit der Tablette α erzielte mittlere Plasmakonzentration wiedergibt,
3. c) die als „Tablette A“ bezeichnete Kurve die mit der Tablette A, die 10 % des oberflächenaktiven Mittels SYNPERIONIC® PE/F127 enthält, erhaltene mittlere Plasmakonzentration wiedergibt,
4. d) die als „Tablette C“ bezeichnete Kurve die mit der Tablette C, die 5 % des oberflächenaktiven Mittels SYNPERIONIC® PE/F127 enthält, erzielte mittlere Plasmakonzentration wiedergibt.

The results obtained in the fasting state are in the attached 1 and those identified in non-fasted condition are included in the attached II reproduced, in which:

1. a) the curve referred to as "gel capsule" represents the average plasma concentration achieved with the preparation in the form of a gel capsule,
2. b) the curve referred to as "tablet α" represents the average plasma concentration achieved with tablet α,
3. c) the curve referred to as "tablet A" represents the mean plasma concentration obtained with tablet A containing 10% of the surfactant SYNPERIONIC® PE / F127,
4. d) the curve referred to as "tablet C" which represents the mean plasma concentration obtained with tablet C containing 5% of the surfactant SYNPERIONIC® PE / F127.

1. 1) feststellen, daß die Anwesenheit des oberflächenaktiven Mittels die biologische Verfügbarkeit des Wirkstoffs in nüchternem Zustand erhöht.
2. 2) die folgenden Vergleichstabellen erstellen, ausgehend von den Ergebnissen der C max und der AUC, die man mit jeder Formulierung bei den nicht nüchternen Freiwilligen erzielt hat im Vergleich zu den entsprechenden Ergebnissen bei den nüchternen Freiwilligen, die als 1 ...isiert werden:

TABELLE I Verhältnis der C max-Werte Behandlung Gelkapsel Tablette α Tablette C Tablette A Nüchtern 1 1 1 1 Nicht nüchtern 12,5 10,3 4,8 2,7 TABELLE II Verhältnis der AUC Behandlung Gelkapsel Tablette α Tablette C Tablette A Nüchtern 1 1 1 1 Nicht nüchtern 16,7 8,9 5.3 3.2 In these curves you can in particular:

1. 1) find that the presence of the surfactant increases the bioavailability of the drug in a fasted state.
2. 2) Compile the following comparison tables, based on the results of C max and AUC achieved with each formulation on non-fasting volunteers compared to the corresponding results in fasting volunteers, which are reported as 1:

TABLE I Ratio of C max values treatment gel capsule Tablet α Tablet C Tablet A Sober 1 1 1 1 Not sober 12.5 10.3 4.8 2.7 TABLE II Ratio of AUC treatment gel capsule Tablet α Tablet C Tablet A Sober 1 1 1 1 Not sober 16.7 8.9 5.3 3.2

These Tables show that the surfactant leads to a reduction of the maximum plasma concentrations of the drug achieved in non-fasting volunteers compared to the fasted volunteers by a factor of 2 to 5 (Table I).

Similarly, one can conclude that the significant variations in bioavailability measured with the surfactant-free formulations can be reduced by a factor of 1.5 to 5 (Table II).

The following examples illustrate the invention.

EXAMPLE 1

Tablet containing the hydrochloride of dronedarone

The following ingredients are used to prepare tablets of the hydrochloride of dronedarone of the following composition: ingredients mg % Hydrochloride of dronedarone (equivalent to 400 mg of the base) 426 65.5 methylhydroxypropylcellulose 21.1 3.25 Lactose monohydrate 46,55 7.2 corn starch 45.5 7 polyvinylpyrrolidone 65 10 Poloxamer 407 40 6.15 Anhydrous colloidal silica 2.6 0.4 magnesium stearate 3.25 0.5 650 100

Here, the following procedure is used:

724.2 g of the hydrochloride of dronedarone, 35.9 g of methylhydroxypropylcellulose are mixed. 79.1 g of lactose monohydrate, 77.4 g of corn starch and 82.9 g of polyvinylpyrrolidone after sieving.

The mixture is moistened with 68 g Poloxamer 407 (SYNPERONIC® PE / F127) in solution in 408 g of purified water and granulated. The wet mass is dried at a temperature in the range of 50 ° C and calibrated on a sieve with a mesh opening of 1.250 mm. The grains calibrated in this way are mixed with 27.6 g of polyvinylpyrrolidone, 4.4 g of anhydrous colloidal silica and 5.5 g of magnesium stearate and the final mixture is compressed in an amount of 650 mg per unit.

EXAMPLE 2

Tablets containing the hydrochloride of dronedarone

Dronedarone hydrochloride tablets of identical formulation to those of Example 1 are prepared using the following procedure:

724.2 g of the hydrochloride of dronedarone, 35.9 g of methylhydroxypropylcellulose, 79.1 g of lactose monohydrate, 77.4 g of corn starch, 82.9 g of polyvinylpyrrolidone and 68 g of poloxamer 407 (SYNPERONIC® PE / F127) are mixed according to Seven. The mixture is then wetted with purified water and the process is then continued as described in Example 1 to give tablets weighing 650 mg per unit.

EXAMPLE 3

Tablets containing the hydrochloride of dronedarone

Tablets containing the hydrochloride of dronedarone of a formulation identical to those in Example 1 are prepared using the following procedure:

724.2 g of the hydrochloride of dronedarone, 79.1 g of lactose monohydrate, 77.4 g of corn starch are mixed. 82.9 g of polyvinylpyrrolidone and 68 g of poloxamer 407 (SNYPERONIC® PE / F127) after sieving. This mixture is moistened with 35.9 g of methylhydroxypropylcellulose in solution in 408 g of purified water and granulated. The wet mass is dried at a temperature in the range of 50 ° C and calibrated on a sieve with a mesh size of 1250 mm. The grains thus obtained are mixed with 27.6 g of polyvinylpyrrolidone, 4.4 g of anhydrous colloidal silica and 5.5 g of magnesium stearate and the final mixture is compressed into units having a weight of 650 mg.

EXAMPLE 4

Tablets containing the hydrochloride of dronedarone

Tablets containing the hydrochloride of dronedarone of the following composition are prepared: ingredients mg % Hydrochloride of dronedarone (equivalent to 400 mg of the base) 426 65.5 Microcrystalline cellulose 65 10 Anhydrous colloidal silica 2.6 0.4 Anhydrous lactose 42.65 6.6 polyvinylpyrrolidone 13 2 Poloxamer 407 40 6.15 Macrogol 6000 57.5 8.85 magnesium stearate 3.25 0.5 650 100 using the following procedure:

724.2 g of the hydrochloride of dronedarone, 110.5 g of microcrystalline cellulose, 2.2 g of anhydrous colloidal silica, 72.5 g of anhydrous lactose, 22.1 g of polyvinylpyrrolidone, 68 g of poloxamer 407 (SYNPERONIC® PE / F127) and 97.8 g of Macrogol 6000. With slow stirring, the temperature of the mixture is heated to 65 ° C in a thermostated container. This mixture is granulated with rapid stirring, cooled to room temperature and then calibrated. The calibrated granules are mixed with 2.2 g of anhydrous colloidal silica and 5.5 g of magnesium stearate and the final mixture is compressed to form units having a weight of 650 mg.

This granulation process can also be carried out in a device with an air circulation bed.

EXAMPLE 5

Tablet containing the hydrochloride of dronedarone

Tablets containing the hydrochloride of dronedarone of a formulation identical to that of Example 4 are prepared by the following procedure:

724.2 g of the hydrochloride of dronedarone, 110.5 g of microcrystalline cellulose, 2.2 g of anhydrous colloidal silica, 72.5 g of anhydrous lactose, 22.1 g of polyvinylpyrrolidone, 68 g of molten poloxamer 407 (SYNPERONIC® PE / F127 ) and 97.8 g of molten macrogol 6000.

The procedure is then as described in Example 4 to obtain tablets having a weight of 650 mg per unit.

EXAMPLE 6

Tablets containing the hydrochloride of dronedarone

Tablets containing the dronedarone hydrochloride of a formulation identical to that of Example 4 are prepared, substituting an equivalent amount of Poloxamer 407 for Macrogol 6000, using the following procedure:

724.2 g of the hydrochloride of dronedarone are mixed. 110.5 g of microcrystalline cellulose, 2.2 g of anhydrous colloidal silica, 72.5 g of anhydrous lactose, 22.1 g of polyvinylpyrrolidone and 166.7 g of Poloxamer 407 (SYNPERONIC® PE / F127) after calibration.

The procedure is then as described in Example 4 to obtain tablets having a weight of 650 mg per unit.

EXAMPLES 7 and 8

Using the procedures described above, tablets of the following composition are prepared: a) ingredients mg Hydrochloride of dronedarone (equivalent to 400 mg of the base) 426 Microcrystalline cellulose 26 corn starch 45.5 polyvinylpyrrolidone 65 Poloxamer 407 40 Anhydrous colloidal silica 2.6 magnesium stearate 3.25 Lactose monohydrate 41,65 650 b) ingredients mg Hydrochloride of dronedarone (equivalent to 400 mg of the base) 213 Microcrystalline cellulose 13 corn starch 22,75 polyvinylpyrrolidone 32.5 Poloxamer 407 20 Anhydrous colloidal silica 1.3 magnesium stearate 1.625 Lactose monohydrate 20.825 325

Claims (11)

A solid pharmaceutical preparation comprising a benzofuran derivative having an antiarrhythmic activity which is adapted to be administered orally, characterized by comprising a benzofuran derivative having antiarrhythmic activity or one of its pharmaceutically acceptable salts as the active ingredient and a hydrophilic nonionic pharmaceutically acceptable surfactant Combined with one or more pharmaceutical carrier materials, characterized in that the benzofuran derivative having antiarrhythmic activity is dronedarone or one of its pharmaceutically acceptable salts. Pharmaceutical preparation according to Claim 1 characterized in that the pharmaceutically acceptable salt is the hydrochloride. Pharmaceutical preparation according to one of Claims 1 to 2 characterized in that the hydrophilic nonionic surfactant is selected from poloxamers, polyethoxylated castor oils, ethoxylated polysorbates and polyethylene hydroxystearates. Pharmaceutical preparation according to Claim 3 characterized in that the hydrophilic nonionic surfactant is selected from poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and the products CREMOPHOR® RH 40 or SOLUTOL® HS15. Pharmaceutical preparation according to Claim 3 or 4 characterized in that the hydrophilic nonionic surfactant is poloxamer 407. Pharmaceutical preparation according to one of Claims 1 to 5 , characterized in that the hydrophilic nonionic agent is present in an amount of 1% to 50%, based on the weight of the active ingredient in the form of the base. Pharmaceutical preparation according to Claim 6 in the form of a tablet or gel capsule, characterized in that the hydrophilic nonionic surfactant is present in an amount of 1% to 20%, based on the weight of the active ingredient in the form of the base. Pharmaceutical preparation according to Claim 7 in the form of tablets or gel capsules, characterized in that the hydrophilic nonionic surfactant is present in an amount of 5% to 15%, based on the weight of the active ingredient in the form of the base. Pharmaceutical preparation according to one of Claims 1 to 8th , characterized in that it contains 50 to 500 mg of the active ingredient per administration unit. Pharmaceutical preparation according to Claim 9 in the form of tablets or gel capsules, characterized in that it contains 200 to 400 mg of the active ingredient per administration unit. Pharmaceutical preparation according to one of Claims 1 to 10 in the form of tablets or gel capsules, characterized in that it contains per administration unit 200 to 400 mg of the active ingredient, calculated in the form of the base, and 10% by weight of the hydrophilic, nonionic surfactant, based on the active ingredient in the form of the base ,

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